Experimental HIV vaccines show promise in early safety test

New HIV vaccines have shown promise in studies with lab animals and human volunteers, pointing to a potential way of preventing the lifelong viral disease.

These experimental vaccines are built upon mRNA technology and several triggered potent immune responses in these early tests, while also causing few side effects.

Scientists described the new vaccines in a pair of studies published Wednesday (July 30) in the journal Science Translational Medicine. The first study tested a few vaccines in rabbits and monkeys, and the promising results of that work led to further development of the shots and the subsequent human trial. The trial included over 100 healthy human volunteers and tested three vaccines similar to those tested in animals.

The effort "marks significant progress in the global effort to develop a safe and effective HIV vaccine that prevents infection," said Seth Cheetham, director of the Australian mRNA Cancer Vaccine Centre and deputy director of the BASE mRNA manufacturing facility at the University of Queensland.

"While drugs for HIV treatment and prevention have transformed the lives of people living with HIV, an effective vaccine is still urgently needed," Cheetham, who was not involved in the work, told Science Media Exchange.

Over the past decade, the annual rate of new human immunodeficiency virus (HIV) infections has fallen significantly, according to the World Health Organization, but, each year, many hundreds of thousands still occur. Globally, an estimated 1.3 million people acquired HIV in 2024, including about 120,000 children. An HIV vaccine could be transformative if, in just a few doses, it could raise the immune system's ability to block the virus from taking hold in the first place.

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Currently, preventive medications for HIV must be taken on an ongoing basis — either daily, every other month or twice yearly. This can pose a particular challenge in areas with limited health care resources and infrastructure. Many scientists think a vaccine will be the key to ending the HIV/AIDS epidemic worldwide, because such a tool could efficiently stymie new infections and curb further spread of the disease.

But crafting an HIV vaccine is very challenging. The virus expertly evades the immune system by donning disguises, and it mutates rapidly, constantly switching up its look. Ideally, HIV vaccines will trigger the production of elusive "broadly neutralizing antibodies" — proteins that target relatively immutable bits of the virus that look similar across many strains and can block infections, thus offering wide-ranging protection.

Scientists are exploring different strategies to trigger that protection. On that front, the researchers behind the new studies turned to messenger RNA (mRNA), a molecule that serves as instructions for cells to make proteins. They designed their experimental vaccines to carry directions for a complex of proteins found on the surface of HIV. Called the "envelope trimer," this complex enables the virus to grab the surface of human immune cells and invade those cells.

Once injected into the body, the vaccines prompt cells to build one of two versions of the envelope trimer: one that exits the cell and floats away, and another that stays bound to the surface of the cell. The free-floating version has been targeted in prior HIV vaccines studies, but previously hasn't produced adequate neutralizing antibodies, the study authors noted.

They think this is because, on the surface of a real HIV particle, the base of the trimer is embedded inside the virus and thus hidden from view. They anticipated that the latter version of the trimer — the one that stays stuck to the cell — would trigger better neutralizing responses that take aim at other parts of the complex, rather than the base.

That turned out to be the case in both the animal study and the early clinical trial.

For the human trial, the researchers recruited 108 healthy people ages 18 to 55, split them into three groups, and gave each group one of three mRNA vaccines. One vaccine encoded a free-floating trimer, while the latter two encoded different bound versions of the structure. Each participant received three doses of their assigned vaccine: one at the initial visit, another two months later, and a final dose six months after the first.

As in the animal tests, the bound trimers elicited stronger signs of protection than the free-floating trimer did. The bound-trimer vaccines produced neutralizing antibodies in 80% of those vaccinated, while the free-floating-trimer vaccine triggered the same response in only 4% of the recipients.

Related: In a 1st, HIV vaccine triggers rare and elusive antibodies in humans

The bound-trimer vaccines also "generated strong memory responses, meaning the body would be better prepared to fight off HIV even long after vaccination," Cheetham noted. This would be thanks to antibody-producing memory B cells, which persist for a long time to help mount quick immune responses against germs they've encountered in the past, either through infection or vaccination.

The human trial was primarily designed to look at the safety of the vaccines, and they were "well tolerated overall." They triggered mostly mild and transient side effects, such as fatigue, achiness, headache, chills, nausea and injection-site pain. However, hives, also called urticaria, were seen in seven participants, which the authors noted was "a far higher frequency than reported with COVID-19 mRNA vaccines." Several of the affected individuals experienced the skin reaction for months.

"While most adverse reactions were mild and treatable, several people experienced a skin reaction," Cheetham said. "If these side effects can be reduced in next-generation versions and the results hold up in larger real-world studies in the community, mRNA vaccines could be a transformative tool in the fight against HIV."

The trial had several other limitations. First, it was open-label, meaning the researchers and vaccine recipients knew which shots were being given, which can potentially bias the results. In addition, the vaccines were not specifically designed to make broadly neutralizing antibodies that can handle many strains but rather neutralizing antibodies that can tackle only select strains.

Nonetheless, the trial results provide insight into the safety and efficacy of mRNA vaccines that code for HIV envelope trimers, the researchers noted. It should inform future efforts to refine these vaccines so they trigger more broadly protective antibody responses.